CERT1 mutations perturb human development by disrupting sphingolipid homeostasis

Gehin C, Lone MA, Lee W, Capolupo L, Ho S, Adeyemi AM, Gerkes EH, Stegmann AP, López-Martín E, Bermejo-Sánchez E, Martínez-Delgado B, Zweier C, Kraus C, Popp B, Strehlow V, Gräfe D, Knerr I, Jones ER, Zamuner S, Abriata LA, Kunnathully V, Moeller BE, Vocat A, Rommelaere S, Bocquete JP, Ruchti E, Limoni G, Van Campenhoudt M, Bourgeat S, Henklein P, Gilissen C, van Bon BW, Pfundt R, Willemsen MH, Schieving JH, Leonardi E, Soli F, Murgia A, Guo H, Zhang Q, Xia K, Fagerberg CR, Beier CP, Larsen MJ, Valenzuela I, Fernández-Álvarez P, Xiong S, Śmigiel R, López-González V, Armengol L, Morleo M, Selicorni A, Torella A, Blyth M, Cooper NS, Wilson V, Oegema R, Herenger Y, Garde A, Bruel AL, Tran Mau-Them F, Maddocks AB, Bain JM, Bhat MA, Costain G, Kannu P, Marwaha A, Champaigne NL, Friez MJ, Richardson EB, Gowda VK, Srinivasan VM, Gupta Y, Lim TY, Sanna-Cherchi S, Lemaitre B, Yamaji T, Hanada K, Burke JE, Jakšić AM, McCabe BD, De Los Rios P, Hornemann T, D'Angelo G, Gennarino VA (2023)

Publication Type: Journal article

Publication year: 2023


Book Volume: 133

Journal Issue: 10

DOI: 10.1172/JCI165019


Neural differentiation, synaptic transmission, and action potential propagation depend on membrane sphingolipids, whose metabolism is tightly regulated. Mutations in the ceramide transporter CERT (CERT1), which is involved in sphingolipid biosynthesis, are associated with intellectual disability, but the pathogenic mechanism remains obscure. Here, we characterize 31 individuals with de novo missense variants in CERT1. Several variants fall into a previously uncharacterized dimeric helical domain that enables CERT homeostatic inactivation, without which sphingolipid production goes unchecked. The clinical severity reflects the degree to which CERT autoregulation is disrupted, and inhibiting CERT pharmacologically corrects morphological and motor abnormalities in a Drosophila model of the disease, which we call ceramide transporter (CerTra) syndrome. These findings uncover a central role for CERT autoregulation in the control of sphingolipid biosynthetic flux, provide unexpected insight into the structural organization of CERT, and suggest a possible therapeutic approach for patients with CerTra syndrome.

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Involved external institutions

Universität Leipzig DE Germany (DE) Universitätsklinikum Leipzig DE Germany (DE) Genuity Science IE Ireland (IE) École Polytechnique Fédérale de Lausanne (EPFL) CH Switzerland (CH) Universitätsspital Zürich (USZ) CH Switzerland (CH) Maastricht University Medical Center (UMC+) NL Netherlands (NL) Research Institute for Rare Diseases / Instituto de Investigación de Enfermedades Raras (IIER) ES Spain (ES) National Centre for Inherited Metabolic Disorders (NCIMD) IE Ireland (IE) Consiglio Nazionale delle Ricerche (CNR) / National Research Council of Italy IT Italy (IT) University of Victoria (UVic) CA Canada (CA) Central South University CN China (CN) University of Calgary CA Canada (CA) University Medical Center Groningen (UMCG) / Universitair Medisch Centrum Groningen NL Netherlands (NL) SIB Swiss Institute of Bioinformatics / SIB Institut Suisse de Bioinformatique / SIB Istituto Svizzero di Bioinformatica / SIB Schweizerisches Institut für Bioinformatik CH Switzerland (CH) Freie Universität Berlin DE Germany (DE) Radboud University Nijmegen Medical Centre / Radboudumc of voluit Radboud Universitair Medisch Centrum (UMC) NL Netherlands (NL) Birmingham Women's and Children's NHS Foundation Trust GB United Kingdom (GB) Newcastle upon Tyne Hospitals NHS Foundation Trust GB United Kingdom (GB) University Medical Centre Utrecht (UMC Utrecht) NL Netherlands (NL) Genetica AG CH Switzerland (CH) Centre hospitalier universitaire (CHU) de Dijon Bourgogne FR France (FR) Université Bourgogne Franche-Comté FR France (FR) Columbia University Irving Medical Center (CUIMC) US United States (USA) (US) University of Zurich / Universität Zürich (UZH) CH Switzerland (CH) University of Alberta CA Canada (CA) University of Padua / Universita degli Studi di Padova IT Italy (IT) Azienda Provinciale per i Servizi Sanitari IT Italy (IT) Fondazione Istituto di Ricerca Pediatrica Città della Speranza (IRP) IT Italy (IT) Odense Universitetshospital (OUH) DK Denmark (DK) Vall d'Hebron University Hospital / Hospital Universitari Vall d'Hebron ES Spain (ES) Tongji University / 同济大学 CN China (CN) Ospedale Sant'Anna IT Italy (IT) Telethon Institute of Genetics and Medicine (TIGEM) IT Italy (IT) NHS Grampian GB United Kingdom (GB) Medical University of South Carolina (MUSC) US United States (USA) (US) Indira Gandhi Institute of Child Health IN India (IN) Columbia University US United States (USA) (US) National Institute of Infectious Diseases, Japan (NIID) JP Japan (JP) Wrocław Medical University / Uniwersytet Medyczny we Wrocławiu PL Poland (PL) Hospital Clínico Universitario Virgen de la Arrixaca ES Spain (ES) Quantitative Genomic Medicine Laboratories, S.L. ES Spain (ES) The Hospital for Sick Children (SickKids) CA Canada (CA)

How to cite


Gehin, C., Lone, M.A., Lee, W., Capolupo, L., Ho, S., Adeyemi, A.M.,... Gennarino, V.A. (2023). CERT1 mutations perturb human development by disrupting sphingolipid homeostasis. Journal of Clinical Investigation, 133(10). https://doi.org/10.1172/JCI165019


Gehin, Charlotte, et al. "CERT1 mutations perturb human development by disrupting sphingolipid homeostasis." Journal of Clinical Investigation 133.10 (2023).

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